This is a proposal to continue funding for a Program to study the molecular mechanisms involved in the induction and maintenance of immune system unresponsiveness and tolerance. Three investigators are unified by the common theme that tolerance is a complex process in which the inherent responsiveness of immune cells, as well as interactions with their anatomical microenvironment, play pivotal roles in determining responsiveness to self- and pathogen-associated antigens. In keeping with the overall theme of the Program Project, the projects proposed in this renewal will consider mechanistic aspects of tolerance in the context of the interactive nature of the immune system. Accomplishments by the individual investigators in this Program during the last funding period include the design and characterization of experimental models that are now amenable to meaningful mechanistic analysis. These are intended to provide methodologies and insights that will continue to bridge the three projects, thereby facilitating synergy and increased scientific scope to the progress of the individual laboratories. Dr. Mark Greene has been replaced by a new member of the Program, Dr. Yongwon Choi. Dr. Choi will study the role of TRANCE in peripheral T cell homeostasis and unresponsiveness to endogenous antigen. An administrative core will provide budget oversight, secretarial support for manuscript preparation and progress reports, as well as logistical support for scheduling investigator meetings and travel arrangements of consultants. The past and future integration of the three laboratories will enhance the scientific quality and productivity to a degree that results in progress that will be greater than the sum of the individual laboratories.